Agent for treating cor pulmonale

ABSTRACT

The present invention relates to an agent for treating cor pulmonale containing as an active ingredient a prostaglandin I 2  derivative represented by the following formula, or a pharmacologically acceptable salt thereof. The agent exhibits excellent effects in oral or parenteral administration. ##STR1##

This application is a National Stage filing under 37 U.S.C. § 371 ofPCT/JP96/00443, filed Feb. 27, 1996.

TECHNICAL FIELD

The present invention relates to an agent for treating cor pulmonalecomprising a prostaglandin I₂ derivative such as, for example,beraprost, or a salt thereof as an active ingredient.

BACKGROUND ART

Cor pulmonale develops a disease condition in which an increase in thepulmonary vascular resistance due to an organic or functionalabnormality of the lungs causes right ventricular pressure overload,resulting in right ventricular hypertrophy and further right ventricularinsufficiency. Cor pulmonale is caused by various diseases, the criticalmechanism of ventricular hypertrophy is not clarified, and no curativemeans is established. Although cor pulmonale is treated by causaldisease treatment (including oxygen therapy) or using a diuretic andcardiotonic, an effective curative means has not yet been established.

On the other hand, prostaglandin I₂ (PGI₂, prostacyclin) which is knownas a substance having the strong actions of inhibiting plateletaggregation and dilating the peripheral vessel (refer to "Nature" Vol.268, p688, 1976) has an unstable exoenol structure, and thus PGI₂ isvery unstable in a neutral aqueous solution and is converted into 6-oxoPGF₁ α which has substantially no physiological activity. Thisinstability of PGI₂ brings about an important problem in utilizing thiscompound as a medicine. The PGI₂ is also unstable in vivo and thus hasthe fault that its physiological action has no persistency. JapaneseExamined Patent Publication No. 1-53672 discloses, as compounds in whichthe faults of PGI₂ are significantly improved, PGI₂ derivatives having askeleton in which the structure of the exoenol ether portion, that is acharacteristic structure of PGI₂, is converted into an inter-m-phenylenetype. However, this publication does not suggest the curative effects ofthose derivatives on cor pulmonale, and it has not yet been known thatthe PGI₂ derivatives have the curative effects on cor pulmonale.

As a result of extensive research for developing an agent for treatingcor pulmonale having excellent efficacy and practicability, theinventors found that the compounds used in the present invention havethe significant effect of ameliorating the condition of cor pulmonale,resulting in the achievement of the present invention.

DISCLOSURE OF THE INVENTION

The present invention provides an agent for treating cor pulmonalecomprising as an active ingredient a 5,6,7-trinor-4,8-inter-m-phenyleneprostaglandin I₂ derivative or a pharmacologically acceptable saltthereof represented by the following formula (I): ##STR2## wherein R₁ ishydrogen, a carboxyl group or a functional derivative thereof, --CH₂ OH,or a pharmacologically acceptable cation;

A is (1) --(CH₂)_(n) --, (2) --(CH₂)_(m) --CH═CH--(CH₂)_(p) --, (3)--(CH)_(m) --C.tbd.C--(CH₂)p-- or (4) --CH₂ --O--CH₂ -- (wherein n is aninteger of 0 to 3, and each of m and p is 0 or 1):

R₂ is (1) a straight chain or branched alkyl group having 5 to 10 carbonatoms, (2) --Ct H2t--OR₃ (wherein t indicates an integer of 1 to 5, andR₃ indicates a straight chain or branched alkyl group having 1 to 5carbon atoms, or a phenyl group), (3) --Ct H2t--CH═C (R₄) (R₅) (whereint indicates the same as defined above, and R₄ and R₅ each indicatehydrogen, a methyl group, an ethyl group, a propyl group or a butylgroup); or (4) --Ct H2t--C.tbd.C--R₆ (wherein t indicates the same asdefined above, and R₆ indicates hydrogen, a methyl group or an ethylgroup), and formula (I) indicates d-, l- and dl-forms.

BEST MODE FOR CARRYING OUT THE INVENTION

The inventors of this invention have already found prostaglandin I₂derivatives are effective as an antiulcer agent, an anti-thrombogenicagent, an antihypertensive agent, and an antiasthmatic agent (JapaneseExamined Patent Publication No. 1-53672).

However, this publication does not suggest that these derivatives havethe curative effect on cor pulmonale, and it has not yet been known thatthe prostaglandin I₂ derivatives have the effect of ameriolating thecondition of cor pulmonale. The inventors of this invention first foundthe effectiveness of the derivatives as an agent for treating corpulmonale.

In compounds represented by the above formula (I), R₁ is preferably acarboxyl group or a functional derivative thereof indicated by --COOR₇(wherein R₇ is an ester residue, specifically, methyl, ethyl or apharmacologically acceptable cation such as an alkaline or alkalineearth metal such as sodium, potassium or calcium, an amine such asmono-, di- or trimethylamine, methyl piperidine, mono-, di- ortriethanolamine, lysine, or basic amino acid); A is preferably (1)--(CH₂)_(n) --, (2) --(CH₂)_(m) --CH═CH--(CH₂)_(p) --, (3) --(CH)_(m)--C.tbd.C--(CH₂)p-- or (4) --CH₂ --O--CH₂ -- (wherein n is an integer of2 to 3, and each of m and p is 0 or 1); R₂ is (1) a straight chain orbranched alkyl group having 5 to 7 carbon atoms, (2) --Ct H2t--OR₃(wherein t indicates an integer of 1 to 3, and R₃ indicates a straightchain or branched alkyl group having 2 to 4 carbon atoms, or a phenylgroup), (3) --Ct H2t--CH═C (R₄) (R₅) (wherein t indicates an integer of1 to 3, and R₄ and R₅ each indicate hydrogen, a methyl group, an ethylgroup, a propyl group or a butyl group); or (4) --Ct H2t--C.tbd.C--R₆(wherein t indicates an integer of 1 to 3, and R₆ indicates hydrogen, amethyl group or an ethyl group). Formula (I) indicates d-, l- anddl-forms. In R₂, --Ct H2t-- represents a straight chain or branchedalkylene group.

Of the above-described compounds, the following compound, beraprost, ora salt thereof is preferably used. ##STR3## The compounds represented byformula (I) can be produced by, for example, the method disclosed inJapanese Examined Patent Publication No. 1-53672.

Oral or parenteral administration of the compounds represented byformula (I) brings about the significant curative effect on corpulmonale.

Cor pulmonale develops a cardiac disorder secondarily caused by variouspulmonary diseases and pulmonary vascular diseases in thepathophysiological state wherein hypoxemia (coexisting withhypercapnemia) resulting from pulmonary insufficiency continues, therebycausing right ventricular pressure overload (an increase in work load ofthe right ventricle). When this state continues, right ventricularhypertrophy and right ventricular failure arise. Cor pulmonale isclassified into acute, subacute and chronic cor pulmonale. Although thecompounds represented by formula (I) of the present invention areeffective against acute, subacute and chronic cor pulmonale, thecompounds are particularly effective against chronic cor pulmonale.

A typical causal disease of acute cor pulmonale is pulmonary embolismwhich causes significant dilation of the right ventricle without rightventricular hypertrophy, resulting in right ventricular failure.Although causes of subacute cor pulmonale include multiple andrepetitive minor pulmonary embolism, dispersion of cancer to the lungs,and compression of the pulmonary main artery due to a tumor, etc., thecondition thereof is similar to acute cor pulmonale. Chronic corpulmonale is frequently caused by a chronic obstructive lung disease.

Examples of causal diseases of cor pulmonale include pulmonary embolism,dispersion of cancer to the lungs, pulmonary tuberculosis, compressionof the pulmonary main artery due to a tumor, pulmonary infarction,diseases which cause primary disorder of the passage of air through thelungs and pulmonary alveoli (for example, chronic bronchitis, bronchialasthma, pulmonary emphysema, pulmonary fibrosis, pulmonarygranulomatosis and humectation, pulmonary abscission, congenitalpulmonary cyst, and height hypoxia), diseases causing primary disorderof the thoracic motion (for example, kyphyosis and other thoracicdeformity, pleural fibrosis, chronic nerve-muscular atrophy, obesityaccompanied with alveolar hypoventilation, and cataplectic alveolarhypoventilation), diseases causing primary disorder of the pulmonaryvessels (for example, primary disorder of the aterial paries, thromboticdiseases, embolism, mediastinal tumor, aneurysm, and compression of thepulmonary main artery and veins due to granulomatosis or fibrosis).

The agent for treating cor pulmonale of the present invention is usednot only for treating cor pulmonale but also for preventing corpulmonale.

The compound represented by formula (I) is administered to an adult oneto three times a day in a dosage of 0.01 to 100 mg/person.

The agent for treating cor pulmonale of the present invention maycomprise at least one of the compounds represented by formula (I) orsalts thereof, or further contain the additives below so that the agentin a solid state can orally be administered.

Examples of such additives include excipients such as starch, lactose,sucrose, grape sugar, mannitol, calcium carbonate, calcium sulfate, andthe like; binders such as starch, dextrin, gum arabic, traganth, methylcellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohols and thelike; disintegrators such as starch, polyvinyl pyrrolidone, crystallinecellulose and the like; lubricants such as magnesium stearate, talc andthe like; colorants; flavors; and the like.

The compounds represented by formula (I) used in the present inventioncan be used in various conventional dosage forms such as tablets,sugar-coated tablets, powders. granules, troches, capsules, pills,syrup, and the like. The compounds may be parenterally administered inthe form of a sterilized solution, and other solutes such as sodiumchloride or glucose in an amount sufficient to prepare an isotonicsolution can also be used. Since the agent for treating cor pulmonale ofthe present invention has the stable chemical structure, it has nodifficult in preparation and can be administered in the foregoing dosageforms for oral administration and a wide verity of other dosage formssuch as an injection, a suppository, etc.

EXAMPLE

Although it will be described with reference to the following compound 1beraprost sodium (referred to as "BPS" hereinafter) as an example thatthe compounds represented by formula (I) have the effect of treating corpulmonale, the compounds are not limited to this. ##STR4##

Example 1

Model Test of Monocrotalin-Induced Disease

Monocrotalin was subcutaneously administered to 7-week-old SD male rats,and, 7 days after the administration, compound 1 was then continuouslyorally administered to the rats for 14 days to examine the effect oftreating cor pulmonale. Compound 1 was used as a test compound. Afterthe completion of the test, the rats were killed, and the weight ratioof the right ventricle of the heat, {weight of the rightventricle/(weight of the left ventricle+weight of the septum)×100(%)},was determined.

BPS's Action on Weight Ratio (%) of Right Ventricle/[LeftVentricle+Septum] of Monocrotalin-administered Rats

    ______________________________________                                                           mean ± S.E.M.                                           ______________________________________                                        Normal               26.8 ± 1.1**                                            Control 50.0 ± 2.9                                                         BPS 0.01 mg/kg 42.9 ± 2.7                                                  BPS 0.03 mg/kg 36.1 ± 2.6**                                                BPS 0.1 mg/kg 38.9 ± 3.3*                                                ______________________________________                                         Statistical significant difference: *p < 0.05, **p < 0.01 vs. control    

It was confirmed that compound 1 significantly depress an increase inthe weight ratio of the right ventricle induced by monocrotalin, andthus has the effect of treating cor pulmonale.

Example 2

Model Test of Interleukin-6-Induced Disease

Interleukin 6 was subcutaneously administered to 7-week-old SD male ratsfor 6 days, and, 2 days after the administration, compound 1 was thencontinuously orally administered to the rats for 5 days to examine theeffect of curing cor pulmonale. Compound 1 was used as a test compound.After the completion of the test, the rats were killed, and the weightratio of the right ventricle of the heat, {weight of the rightventricle/(weight of the left ventricle+weight of the septum)×100(%)},was determined.

BPS's Action on Weight Ratio (%) of Right Ventricle/[LeftVentricle+Septum] of IL-6-administered Rats

    ______________________________________                                                           mean ± S.E.M.                                           ______________________________________                                        Normal               26.1 ± 0.9**                                            Control 32.2 ± 0.7                                                         BPS 0.01 mg/kg 30.1 ± 1.0                                                  BPS 0.1 mg/kg 29.6 ± 1.0*                                                ______________________________________                                         Statistical significant difference: *p < 0.05, **p < 0.01 vs. control    

It was confirmed that compound 1 significantly depress an increase inthe weight ratio of the right ventricle induced by interleukin 6, andthus has the effect of treating cor pulmonale.

Example 3

Pulmonary Embolism Model Test

Collagen (5 μg/head) and epinephrine (0.6 μg/head) were simultaneouslyinjected into the caudal veins of 7-week-old ddY male mice (27-30 g)obtained from Nippon S.L.C. Co., Ltd. to cause pulmonary embolism. Oneweek after pulmonary embolism was induced, the wet weight/dry weightratio of the lungs and the weight ratio of the right ventricle, {weightof the right ventricle/(weight of the left ventricle+weight of theseptum)×100(%)}, were determined. Compound 1 (0.01 mg/kg, 0.03 mg/kg,0.1 mg/kg) was orally administered every day for 7 days from the dayafter inducing pulmonary embolism.

BPS's action on the wet weight/dry weight ratio of the lungs and theweight ratio of the right ventricle of pulmonary embolism model micesimultaneously administered with collagen and epinephrine.

    ______________________________________                                                 Wet weight/dry weight                                                                      Weight ratio of                                           ratio of lungs right ventricle                                                mean ± S.E.M. mean ± S.E.M. n                                         ______________________________________                                        Normal     3.84 ± 0.01*                                                                              28.2 ± 0.9**                                                                           5                                         Control 3.96 ± 0.04 32.3 ± 0.9 8                                        BPS 0.01 mg/kg 3.92 ± 0.04 30.1 ± 1.4 6                                 BPS 0.03 mg/kg 3.85 ± 0.02* 27.8 ± 1.4 6                                BPS 0.1 mg/kg 3.85 ± 0.02* 27.3 ± 1.1** 6                             ______________________________________                                         Statistical significant difference: *p < 0.05, **p < 0.01 vs. control    

Compound 1 significantly depressed the wet weight/dry weight ratio ofthe lungs and exhibited the effect of inhibiting pulmonary embolism.Compound 1 further significantly depressed the weight ratio of the rightventricle and was thus confirmed to have the effect of treating corpulmonale.

INDUSTRIAL APPLICABILITY

The agent of treating cor pulmonale of the present invention exhibitsexcellent pharmaceutical effects in both oral and parenteraladministration.

What is claimed is:
 1. A method of treating cor pulmonale comprisingadministering to a patient of cor pulmonale an effective amount of a5,6,7-trinor-4,8-inter-m-phenyleneprostaglandin I₂ derivative or apharmacologically acceptable salt thereof represented by the followingformula (I): ##STR5## wherein R₁ is hydrogen, --COOR₇, (wherein R₇ is anester group, or a pharmacologically acceptable cation), --CH₂ OH, or apharmacologically acceptable cation;A is --(CH₂)n--,--(CH₂)m--CH═CH--(CH₂)p--, --(CH)m--C.tbd.C--(CH₂)p-- or --CH₂ --O--CH₂-- (wherein n is an integer of 0 to 3, and each of m and p is 0 or 1),R₂ is (1) a straight chain or branched alkyl group having 5 to 10 carbonatoms, (2) --C_(t) H2_(t) --OR₃ (wherein t indicates an integer of 1 to5, and R₃ indicates a straight chain or branched alkyl group having 1 to5 carbon atoms, or a phenyl group), (3) --C_(t) H2_(t) --CH═C(R₄) (R₅)(wherein t indicates the same as defined above, and R₄ and R₅ eachindicate hydrogen, a methyl group, an ethyl group, a propyl group or abutyl group); or (4) --C_(t) H2_(t) --C.tbd.C--R₆ (wherein t indicatesthe same as defined above, and R₆ indicates hydrogen, a methyl group oran ethyl group); and formula (I) indicates d-, l- and dl-forms.
 2. Themethod of treating cor pulmonale according to claim 1, wherein thecompound represented by formula (I) is: ##STR6##
 3. The method oftreating cor pulmonale according to claim 1, wherein cor pulmonale isacute, subacute or chronic cor pulmonale.
 4. The method of treating corpulmonale according to claim 1, wherein cor pulmonale is chronic corpulmonale.